Drug delivery system using galactoxyloglucan

ABSTRACT

The present invention relates to a pharmaceutical sustained release preparation prepared by using as a sustained release ingredient a partial degradation product of the galactose of a galactoxyloglucan and a method for sustained releasing of a drug thereby. In more detail, it relates to a pharmaceutical sustained release preparation, wherein the sustained release of a drug is effected by utilizing the thermally reversible gel characteristics of the galactose-partial degradation product, which is produced by partial removal of the galactose on the side-chain of a galactoxyloglucan with an enzyme.

TECHNICAL FIELD

The present invention relates to a drug delivery system using agalactoxyloglucan, that is, to a drug sustained release preparationcontaining as a sustained release ingredient a partial degradationproduct of the galactose moiety of a galacto-xyloglucan and a method forthe sustained release of a drug thereby. More particularly, the presentinvention provides a drug sustained release preparation which cangradually release the drug in biobody by utilizing thermally reversiblegel (or thermoreversible gel) behavior of the galactose-partialdegradation product of a galactoxyloglucan, which is produced bypartially removing a galactose moiety on the side-chain from agalactoxyloglucan with an enzyme, and also provides a method ofgradually releasing a drug by using the galactose-partial degradationproduct of a galactoxyloglucan.

PRIOR ART

The so-called drug delivery system (abbreviated as DDS), that is atechnique for maintaining a constant blood level of a drug for a longperiod of time by administrating of a drug into body, or for maintainingan optimal concentration of a drug in the target organ specifically andfurther for a long period of time, is important in order to enhance theeffect of the drug, and to diminish a side effect so as to use the drugsafely. A pharmaceutical preparation defined as a sustained releasepreparation is known as one of such techniques, and the development of asustained release preparation being capable of controlling the releaseof drugs at the most suitable release rate and concentration isimportant no less than the development of a new drug.

Various new forms of a pharmaceutical preparation are known as such adrug sustained release preparation, which include forms approached fromtechnological aspect, such as those utilizing a thin membrane of apolymer or utilizing a deformated surface of a solid material andfurther forms approached from biological aspect, such as those utilizingas a carrier a liposome, an emulsion or a polylactic acid.

As a pharmaceutical preparation being capable of sustaining release of adrug, a hydrogel preparation using various hydrogels as a sustainedrelease ingredient has been proposed, for instance, a hydrogelpreparation comprising a core composed of a drug and a water-solublepolymer, and an outer layer of a base material comprising awater-soluble polymer (JP-A-63-215620), and a composite drug prepared byincorporating a peptide into a polysaccharide (JP-A-5-38635).Furthermore, it is reported to use a suppository using as a sustainedrelease ingredient, Pluronic, a polyoxyethylene-polyoxypropylenecopolymer which is in the form of a sol at a low temperature but isgelled at a body temperature [S. Miyazaki et. al., Chem. Pharm. Bull.,32, 4205 (1984)].

The conventional attempts using a polymer having gelling property as agel base for a drug (a sustained release ingredient) have some problemssuch as a difficulty of the infusion into the body or being painful dueto high viscosity in any dosage form such as oral administration, rectaladministration with a suppository etc. or injection.

A gel base for DDS, which maintains a suitable shape in a body andenables to exhibit the sustained release properties, is desired to havethe characteristic that it has a low viscosity and is liquid or a solwhen infused, and it is thickened and gelled at around the bodytemperature. The above-mentioned synthetic polymer, Pluronic, is knownas such a gel base, but it must be used in a high concentration such as20 to 30% for gelation. On the other hand, for oral administration, thedosage shall be at the most about several hundreds of mg per kg in viewof safety, and the amount in the safe range is not necessarily suitableto the desired sustained release preparation in the scope of safety.

An object of the present invention is to provide a sustained releasepreparation using a natural polysaccharide which is safe for a body as agel base (a sustained release ingredient) for DDS and a method foreffecting sustained release of a drug.

SUMMARY OF THE INVENTION

The gel base (a sustained release ingredient) useful for DDS havepreferably the following characteristics; 1) it is originated fromnature to be safeful for the body, 2) it can be gelled even in a lowconcentration, 3) it has a low viscosity at room temperature and isliquid or a sol when infused and it is thickened and gelled at a bodytemperature within the body. The present inventors have intensivelystudied to produce a gel base satisfying the above characteristics fromnatural polysaccharides which are safe for a body, and as a result, havefound that the partial degradation product of the galactose moiety of agalactoxyloglucan, which is produced by removing a part of galactosemoieties from a galactoxyloglucan (hereinafter, it is optionallyreferred to a merely as “galactose-partial degradation product”), isuseful as a gel base. That is, the present invention provides a drugsustained release preparation which is produced by incorporating of adrug into the galactose-partial degradation product to be used as a gelbase. The present invention provides also a method of controllingrelease of a drug by incorporating the galactose-partial degradationproduct as a sustained release ingredient into a drug-containingpreparation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a result of a test of release of a drug at 37° C. from anindomethacin suppositories which are prepared using a 0.5 W/V %, 1.0 W/V%, or 2.0 W/V % aqueous solution of the galactose-partial degradationproduct (pH 7.2, phosphate buffer) as well as from a commerciallyavailable indomethacin suppository. The vertical axis represents theamount of drug released (%), and the horizontal axis represents time(minute). The symbol —∘— represents the case of the commerciallyavailable indomethacin suppository, and the symbols —⋄—, —□— and —Δ—represent the cases of the indomethacin suppositories prepared from the0.5 W/V %, 1.0 W/V %, and 2.0 W/V % aqueous solutions of thegalactose-partial degradation product, respectively.

FIG. 2 shows a result of a test of release of a drug at 37° C. from atablet comprising diltiazem hydrochloride and the galactose-partialdegradation product. As a control, a commercially available diltiazemhydrochloride tablet was used. The vertical axis represents the drugrelease ratio (%), and the horizontal axis represents time (hour). Thesymbol —□— represents the case of the commercially available tablet, andthe symbol —▪— represents the case of the tablet containing thegalactose-partial degradation product.

FIG. 3 shows a result of a test for absorption of a drug through therectal mucous membrane in rabbits as to an indomethacin suppositoryincorporated with the galactose-partial degradation product and acommercially available indomethacin suppository. The vertical axisrepresents the drug concentration in the plasma (μg/ml), and thehorizontal axis represents time (hour). The symbol —∘— represents thecase of the commercially available indomethacin suppository, and thesymbol —— represents the case of the indomethacin suppository preparedusing a 2.0 W/V % aqueous solution of the galactose-partial degradationproduct.

FIG. 4 shows the change of drug concentration in plasma in rats when amitomycin C-containing gel preparation prepared using a 1.5 W/V %aqueous solution of the galactose-partial degradation product or anaqueous mitomycin C solution was administered into the abdominal cavityof rats. The vertical axis represents the drug concentration in plasma(μg/ml), and the horizontal axis represents time (hour). The symbol —∘—represents the case of administration of the control aqueous solution ofmitomycin C, and the symbol —— represents the case of administration ofthe mitomycin C-containing gel preparation prepared by using a 1.5 W/V %aqueous solution of the galactose-partial degradation product.

FIG. 5 shows the change of drug concentration in ascites in rats when amitomycin C-containing gel preparation prepared using a 1.5 W/V %aqueous solution of the galactose-partial degradation product or anaqueous solution of mitomycin C was administered into the abdominalcavity of rats. The vertical axis represents the drug concentration inthe ascites (μg/ml), and the horizontal axis represents time (hour). Thesymbol —Δ— represents the case of administration of the control aqueoussolution of mitomycin C and the symbol —▴— represents the case ofadministration of the mitomycin C-containing gel preparation prepared byusing the 1.5 W/V % aqueous solution of the galactose-partialdegradation product.

DISCLOSURE OF THE INVENTION

The sustained release preparation of the present invention includes apartial degradation product of the galactose moiety of agalactoxyloglucan as an ingredient for effecting sustained release of adrug, and is prepared by using the galactose-partial degradation productas a gel base, i.e. by incorporating a drug into said gel base and beingformed into the desired dosage form in admixture with a conventionalpharmaceutically acceptable carrier or diluent in a usual manner.

When the preparation of the present invention is administered, thegalactose-partial degradation product incorporated as a drug sustainedrelease ingredient is gelled due to the body temperature and to form amatrix, wherein the drug is embraced, and thereby the release of drug iscontrolled so as to gradually release it, and as a result the desirabledrug level is maintained for a long period of time.

The present invention is explained in more detail below.

The partial degradation product of the galactose moiety of agalactoxyloglucan of the present invention mean the compound, whereingalactose moiety on the side chain are partially removed from agalactoxyloglucan and may be abbreviated as the galactose-partialdegradation product.

Galactoxyloglucan is a constitute component of a cell wall (a primarywall) of a higher plant such as dicotyledon, monocotyledon and it existsas a reserve polysaccharide of a part of plant seeds. Galactoxyloglucanconsists of saccharides selected from glucose, xylose, and galactose,wherein the main chain consists of β-1,4 bonded glucose, and the sidechain consists of xylose and further galactose bonds to the xylose. Thegalactoxyloglucan per se usually does not gel, but it gels in thepresence of a saccharide, an ion, or an alcohol. However, it hasrecently been reported that when the galactose on the side chain of agalactoxyloglucan is removed in a ratio of 30-55%, it induces thermallyreversible gel characteristics, that is, it behaves reversibly gelationby heating and forming of sol by cooling (Shirakawa et. al., AnnualMeeting of Japan Society for Bioscience, Biotechnology, andAgrochemistry, 1995, JP-A-8-283305). However, it has not been known tobe useful as a gel base for DDS.

Galactoxyloglucan used in the present invention includesgalactoxyloglucan originated from any plants; for instance, seeds oftamarind, jatoba and nasturtium, cereals such as soybean, greenbean,kidney beans, rice and barley or skin of fruits (e.g. apple). The mostpreferable one is a galactoxyloglucan obtained from tamarind seed in thepea family because the tamarind seed is the most easily available andhas a large content thereof.

The method of the partial removal of the galactose moiety from agalactoxyloglucan is, for instance, a hydrolysis with a dilutedinorganic acid such as diluted hydrochloric acid, a pyrolysis and anenzymatic hydrolysis, but the former two methods are unsuitable becausethe main chain and a xylose on the side chain are simultaneouslycleaved. Preferred method is an enzymatic hydrolysis, particularly anenzymatic hydrolysis using a β-galactosidase which can cleave galactosespecifically. The enzymatic hydrolysis can be carried out under mildconditions, and further can be carried out the partial removal ofgalactose on the side chain selectively depending to the conditions. Theβ-galactosidase includes any product obtained from plants ormicroorganisms, but preferrable one is an enzyme originated from themicroorganisms such as Aspergillus orizae, or Bacillus circulans, or anenzyme in the seed containing galactoxyloglucan. Commercially availableenzyme products contain occasionally cellulase orisoprimeverose-producing enzyme and hence, if necessity, the enzymes maybe purified to remove those enzymes. The purification may be carriedout, for instance, various kinds of chromatography utilizing differencesin the physical properties such as ion-exchange characteristics,hydrophobic properties, affinity etc., such as ion-exchangechromatography and affinity chromatography.

The method of the partial removal of the galactose moiety of agalactoxyloglucan using enzyme is usually carried out by treating anaqueous solution of the substrate galactoxyloglucan with aβ-galactosidase under the optimum conditions such as the optimalreaction temperature, pH and concentration, and in this case thegalactose may be removed at a constant ratio corresponding to thereaction time. For instance, in the case of a 2% substrateconcentration, it may be carried out under a 0.05% enzymaticconcentration, pH 5˜6 and reaction temperature 50˜55° C . In theenzymatic reaction, the galactose on the side chain is removed partiallywith progressing of the reaction, and where the removal ratio of agalactose reaches to about 30%, the reaction solution is rapidlythickened and gelled. Where the removal ratio of galactose is in therange of 30 to 55%, the galactose-partial degradation product hasreverse thermal gelation characteristics, whereby it is gelled byheating and forms sol by cooling. Where the removal ratio of galactoseis less than 30%, it does not gel, and on the other hand, where theratio is over 55%, it forms a strong gel.

Since the gel base for DDS is required to be soluble in water and to gelat around the body temperature, the galactoxyloglucan used in thepresent invention has a removal rate of galactose in the range of 30 to55%, preferably in the range of 35 to 50%. The galactose-partialdegradation product is usually used in the form of an aqueous solution,and the concentration of the solution varies depending on the removalratio of the galactose and on the desired dosage form, but preferably isin a low concentration such as 0.5˜3.0 W/V %.

The gel base used in the present invention has thermally reversible gelcharacteristics at a low concentration and hence is usable as a base forthe material for controlling release of a drug or a base for apreparation suitable for staying a drug in the body. Besides, the gelbase is a galactoxyloglucan originated from natural products, and henceit is safety to biobodies.

The preparations prepared by using the galactose-partial degradationproduct of the present invention as a gel base can release the druggradually and the release of drug can be controlled by selectingadequately the removal ratio of galactose in the galactose-partialdegradation product and the concentration thereof.

The sustained release preparation of the present invention is preparedin various dosage forms according to the administration routes; forinstance, preparations for oral adminisration such as tablets, capsules,granules, liquid preparations or jelly; suppositories for rectalabsorption; suppositories for vaginal route, patches suitable forabsorptions via percutaneous or mucous membrane route; cataplasms;preparations applicable into oral cavity (troche); dental preparations;liquid preparations or jelly for intraperitoneal administration;injections for intravenous, intramuscular or subcutaneous injection; eyedrops; or nasal drops. These preparations may be prepared byconventional methods [cf, for instance “Recent Techniques forPreparation and their Application”, I. Utsumi etc., Medical Journal,page 157-159 (1983)]. Tablets may be prepared by mixing thegalactose-partial degradation product with a drug and conventionalcarriers for tablets, followed by tabletting the mixture directly with atabletting machine to give the desired tablets. Suppositories andpreparations for intraperitoneal administration are prepared bypreparing an aqueous solution in an adequate concentration (0.5˜3.0 W/V%) of the galactose-partial degradation product in a cold water, addingthereto a drug and kneading the mixture to give a liquid preparation.This liquid preparation can be administered by infusing into the rectumor the abdominal cavity with an infusion syringe, whereby thegalactose-partial degradation product thus infused is gelled by the bodytemperature and the preparation is stayed in the rectum or in theabdominal cavity. Besides, such a liquid preparation may be previouslygelled by heating in a molding vessel, and the resulting gel preparationmay be inserted into the rectum or the abdominal cavity. The patchessuitable for the percutaneous or mucous membrane absorptions areprepared by mixing the galactose-partial degradation product and a drugand optionally other additives, and spreading the mixture onto a supportcloth in an usual manner. In all methods as mentioned above, theproducts can be controlled so that the contents are gelled at around thebody temperature. Since the concentration suitable for gelling thegalactose-partial degradation product is in a low concentration rangesuch as 0.5 to 3.0 W/V %, these preparations may be formulated so as tobe within such a concentration range. The galactose-partial degradationproduct may be used alone as a sustained release ingredient with a drug,but may be used together with other conventional additives such ashydrophilic bases (e.g. polyethylene glycol, sorbitol, dextran etc.),polymers (e.g. polyethylene oxide, methyl cellulose, CMC etc.),surfactants (e.g. higher fatty acid esters), and excipients.

The drugs used in the present invention are not limited in particular,so long as aiming at sustaining release, and include various kinds ofdrugs; for instance, anti-inflammatory agents, antipyretics,antispamodics, analgesics, antituberculosis drugs, drugs for circulatoryorgans, antipsychotic drugs, antihistaminics, vitamins, antiarthritics,hypnotic sedatives, carcinostatic agents, antineoplastic drugs,decongestants, antidiabetics, diuretics, bronchodilators, antitussives,antiarrhythmics, surface anesthesia drugs, antiepileptics, steroids,drugs for digestive organs, central nervous system drugs,anti-hyperlipidemics, antibiotics, diagnostic drug, bowel movementimprovers, antiallergic drugs, agents for applying to epidermics, andophthalmic drugs.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated by means of reference examples andexamples but is not limited thereto.

Reference Example 1

Preparation of the partial degradation product of the galactose moietyof a galactoxyloglucan:

Galactoxyloglucan originated from tamarind seed (Trade name: “GLYROID”,manufactured by DAINIPPON PHARMACEUTICAL CO., LTD.) (120 g) wasdissolved in water (4 kg) with vigorous stirring. The mixture wasmaintained at 55° C. and then adjusted to pH 6 using trisodium citrate,followed by addition of β-galactosidase (Trade name: “Biolacta N5”,manufactured by DAIWA KASEI CO., LTD.) (3.6g), and the mixture wasreacted with stirring for 16 hrs. After the enzyme was inactivated byheating at 95° C. for 30 minutes, the mixture was cooled to roomtemperature and thereto was added an equal amount of ethanol and thenthe mixture was allowed to stand for 1 hr. After the resultingprecipitates were collected by filtration with suction and dried with ablower drier, the precipitates were pulverizated and passed screen togive a powder of the galactose-partial degradation product (the removalratio of galactose: about 44%, 103 g). The removal ratio of galactosewas calculated from an amount of free galactose measured by highperformance liquid chromatography (a connected column: Shodex lonpak KS805+KS802).

Reference Example 2

The gelling properties of the galactose-partial degradation product:

The powdery of the galactose-partial degradation product obtained inReference Example 1 (the removal ratio of galactose: about 44%) wasdispersed and dissolved in a purified water or a phosphate buffer (pH7.2) with stirring under ice-cooling to prepare 0.5 W/V %, 1.0 W/V %,2.0 W/V % and 3.0 W/V % solutions. Such partial degradation productswere gelled at a low concentration (1.0 W/V % or more), and a 2.0 W/V %aqueous solution of the partial degradation product was gelled at about20° C. Besides the each aqueous solution was observed the gellingproperties (sol/gel behavior), under ice-cooling or at 37° C.respectively. The results are shown in Table 1.

TABLE 1 The gelling properties of the galactose-partial degradationproduct Concentration of the aqua. solutions Temperature Sol/Gel W/V%Solvents (° C.) behavior 1.0 Purified water ice-cooling Sol 37 Gel 2.0Purified water ice-cooling Sol 37 Gel 3.0 Purified water ice-cooling Sol37 Gel 0.5 Phosphate buffer, ice-cooling Sol pH 7.2 37 Sol 2.0 Phosphatebuffer, ice-cooling Sol pH 7.2 37 Gel

Example 1

Release properties of drugs in the gel suppository consisting ofindomethacin and the galactose-partial degradation product:

An appropriate amount of the powdery galactose-partial degradationproduct obtained in Reference Example 1 was added in portions to aphosphate buffer (pH 7.2) with stirring under ice-cooling and stirredfor about 1 hr at about 4500 rpm to prepare the 0.5 W/V %, 1.0 W/V % and2.0 W/V % aqueous solutions (the uniform pasty solution) respectively.Test samples were prepared by dissolving indomethacin (25 mg,manufactured by SIGMA CO.) as a controlled drug into the above eachaqueous solution (3 ml) (the drug concentration: 0.83 W/V %). These testsamples were gelled by heating to 37° C. Release of a drug was tested asto the drug (25 mg)-containing test samples. An indomethacin suppository(Trade name: “Hisamitsu IND” manufactured by HISAMITSU PHARMACEUTICALCO., INC.) was used as a controlled sample.

The drug-release test was carried out by using a testing apparatus forrelease test on suppository (manufactured by TOYAMA INDUSTRY CO, LTD.,TMS-103) at 37° C. That is, a phosphate buffer (pH 7.2, 300 ml) was usedas a release solution, and the above test sample and the phosphatebuffer (pH 7.2, 3 ml) were placed into the cell for suppository equippedwith a membrane filter (the pore size: 3.0 μm) and the test was carriedout at 37±0.1° C. The drug concentration in the release solution wasmeasured by a spectrophotometric method (266 nm) with the lapse of timeat a speed of stirring of 100 rpm and a velocity of shaft rotation of 25rpm. The amount of drug in the released solution to that of the drug tobe contained in the specimen suppository was calculated as the amount ofdrug released (%). The results were shown in FIG. 1.

As is clear from FIG. 1, in the suppository on the market (—∘—) the drugwas released in about 100% within lhr, and on the other hand, in the gelsuppositories of the galactose-partial degradation product (0.5 W/V %(—⋄—), 1 W/V % (—□—) and 2 W/V % (—Δ—)) the release rate was less than30% even after lhr and thus the release rate of a drug from the gelpreparations suggests a sustained release. In particular, the gelsuppositories prepared from the 1 W/V % and 2 W/V % aqueous solutionsexhibited excellent sustained release properties.

Example 2

Release of a drug in the tablet consisting of diltiazem hydrochlorideand the galactose-partial degradation product:

Diltiazem hydrochloride (30 mg) on the market [manufactured by WAKO PURECHEMICAL INDUSTRIES, LTD.] and the galactose-partial degradation product(75 mg) obtained in Reference Example 1 were uniformly mixed, and themixture was tabletted directly by a tabletting machine for potassiumbromide (pressure: 200 kg/cm² for 2 minutes) to prepare a tablet(diameter: 10 mm, weight: 105 mg). The drug-relase test of the diltiazemhydrochloride (30 mg)-containing tablet was carried out by thedissolution test as defined in The Pharmacopoeia of Japan XII (arotating basket method) using as a test solution the first solution (pH1.2, 37° C.) in the disintegration test in the Pharmacopoeia of JapanXII at a rotation of 150 rpm. A fixed amount of the test solution wascollected with the lapse of time and the absorbance thereof was measuredat 237 nm and then the concentration of a drug was calculated. Diltiazemhydrochloride on the market was used as a controlled drug. The amount ofthe drug in the test solution to that of the drug contained in thespecimen tablet was calculated as the amount of drug released (%). Theresults are shown in FIG. 2.

As is clear from FIG. 2, the drug release of the tablet in the presentinvention (—▪—) exhibited the same behavior as that of tablet on themarket (—□—).

Example 3

Test of absorption of drug through rectal mucous membrane in rabbit:

1) Behavior of the gel suppository containing no drug of the presentinvention in rectum of rabbit:

A liquid suppository (3 ml), a 2.0 W/V % aqueous solution of thegalactose-partial degradation product obtained in Example 1 whichcontained fluorescein sodium, was administrated by infusion into therectum of a fasted male Japanese white rabbit (body weight: 3.0-4.0 kg)(allowing to take water freely) at a distance of about 2 cm from theanus with a disposyringe connected to a silicone tube (about 3 cm). Thestate of distribution of the suppository was photographed by UVirradiation after 1, 3 and 6 hrs. As a result, it was observed thatevery gel suppositories existed in the rectum in the state of a gel.

2) Test of absorption of a drug in rectal mucous membrane from thedrug-containing gel suppository of the present invention in rabbit:

An indomethacin suppository on the market (Trade name: “Hisamitsu IND”,manufactured by HISAMITSU PHARMACEUTICAL CO., INC.) was administeredinto the rectum of male Japanese white rabbits fasted for 36 hrs (bodyweight: 3.0-4.0 kg, four rabbits) (allowing to take water freely). Onthe other hand, the indomethacin-containing gel suppository (as a sol, 3ml) consisting of a 2.0 W/V % aqueous solution of the galactose-partialdegradation product obtained in Example 1 was administered by infusioninto the rectum of the rabbits at a distance of about 2 cm from an anusthereof with a disposyringe connected to silicone tube (about 3 cm). Inevery cases, a blood sample (about 1 ml) was collected from the ear veinof the rabbit with the lapse of time and a concentration of indomethacinin the plasma was measured by HPLC (high performance liquidchromatography) method. The results are shown in FIG. 3. Besides, Table2 indicates pharmacokinetics parameters obtained from the change of theblood concentration shown in FIG. 3.

TABLE 2 Comparison of the pharmacokinetics parameters n Pharmaceutical(number of Tmax Cmax AUC(0˜6 hr) preparations rabbit) (hr) (μg/ml) (μg ·hr/ml) Suppository on the 4 0.5 8.59 ± 0.49  11.87 ± 0.62 marketSuppository of the 4 0.5 3.54 ± 0.34* 11.36 ± 0.96 present inventionSignificant difference test: *p < 0.01

As is clear from FIG. 3 and Table 2, both the suppository on the marketand the gel suppository of the present invention showed rapidabsorption. T_(max) (a time reached to a maximum plasma concentration)being 0.5 hour, but C_(max) (a maximum plasma concentration) of the gelsuppository of the present invention was a half of that of thesuppository on the market and further the gel suppository of the presentinvention showed more sustained blood concentration than that of thesuppository on market. Besides, as to AUC (area under the curve of thecorrelation of the blood concentration-time) indicating abioavailavility, both suppositories showed almost the same values. Theabove results suggest that the administration of the gel suppository ofthe present invention enables to maintain the effective bloodconcentration of drug for a long time and to have a durability in theamount of drug released. Thus, administration of the gel suppository ofthe present invention enables to diminish the side effect of drugs.

3) Irritation to the rectal mucous membrane by the drug-containing gelsuppository of the present invention in rabbit:

Gel suppositories of the present invention (the 2.0 W/V % aqueoussolution of the galactose-partial degradation product obtained inExample 1) which contained indomethacin or not was each administeredinto the rectum of rabbits, and a histophthological test was done forthe rectal mucous membrane after 6 hrs, but no abnormal phenomenon wasobserved on the rectal tissue and no irritation onto the rectal mucousmembrane was found.

The above results suggest the gel suppository of the present inventionis useful as a base for preparing a sustained release preparationsuitable for rectal administration.

Example 4

For the purpose of the treatment of various tumors such as a peritoneal,or carcinomatous peritonitis there has hitherto been used mitomycin C,an anti-cancer agent. However since the mitomycin C administered intothe abdominal cavity is rapidly transferred to a systemic circulation,it can not exhibit sufficient therapeutic effects. Then, in order toprolong the retention time of mitomycin C in the abdominal cavity, itwas tried to apply the drug-containing gel preparation of the presentinvention, which test was carried out in rats by intraperitonealadministration of the preparation.

A test by intraperitoneal administration in rats:

Male Wistar rats fasted for 18 hours (allowing to take water freely)were used.

1) Gelling properties of the gel preparation containing no drug of thepresent invention in the abdominal cavity:

A 1.5 W/V % aqueous solution of the galactose-partial degradationproduct obtained in Example 1 (4 ml) in the form of a sol, which wascolored with bromothymol blue, was administered by infusion into theabdominal cavity. Then the state of distrubution of the preparation wasobserved for 6 hrs. As a result, it already became gelation in 15minutes after administration. Thus, it was found that the solutionadministered into the abdominal cavity gelled rapidly. Besides, thestate of gelation was kept after 1 hour or even after 6 hrs.

2) A test by intraperitoneal administration of the drug-containing gelpreparation of the present invention into rat:

A 1.5 W/V % aqueous solution (4 ml) of the galactose-partial degradationproduct containing mitomycin C (5 mg/kg) was administered by infusioninto the abdominal cavity of rat, and the concentration of mitomycin Cin plasma or in ascites was measured with the lapse of time by HPLCmethod.

As a control, an equal amount of an aqueous solution containingmitomycin C (5 mg/kg) was used. The measurement of the concentration ofdrug in ascites was done using as an artificial ascites a solution whichwas prepared, when measured, by infusing an isotonic sodium chloridesolution (Sml) into the abdominal cavity and re-sucking. The results areshown in FIG. 4 and FIG. 5.

As is shown in FIG. 4, in the case of administration of the controlaqueous solution (—∘—), blood concentration of the drug reached to theCmax in 30 minutes after administration and thereafter reduced rapidlyand after 3 hrs it was scarcely detected. On the other hand, in the caseof administration of the gel preparation of the present invention (——),the drugs were transferred into the blood more slowly than the case ofthe control aqueous solution. Besides, as is clear from FIG. 5, in thecase of administration of the gel preparation of the present invention(—▴—), the concentration of drugs in ascites was reduced more slowlythan the case of administration of the control aqueous solution (—Δ—)and detected even after 6 hrs.

The above results suggest that an administration by infusion of themitomycin C-containing gel preparation of the present invention enablesto retain the drug in the abdominal cavity for a long time, and hence itis useful as a sustained release preparation.

INDUSTRIAL APPLICATION

The galactose-partial degradation product, which is produced by partialremoval of galactose on the side-chain of a galactoxyloglucan with anenzyme (a removal ratio: 30˜55%), exhibits thermally reversible gelcharacteristics, that is, it gels by heating (around a body temperature)and forms a sol by cooling, and hence, when the galactose-partialdegradation product is used as a sustained release ingredient (as a gelbase) for preparing a sustained release preparation, it is effective forduration of sustained release on the amount of drug released (eluted).Thus, it is very useful as a sustained release ingredient. Further, whenthe galactose-partial degradation product of the present invention isused for preparing tablets, the desired tablets having excellentsustained release properties can easily be prepared by tabletingdirectly the mixture without using any carrier or diluent.

What is claimed is:
 1. A pharmaceutical sustained release preparationcomprising a partial degradation product of the galactose of agalactoxyloglucan, which is produced by subjecting a galactoxyloglucanoriginating from a plant to an enzymatic hydrolysis and to a galactoseremoval ratio of 30-55%, a pharmaceutically active compound andoptionally a pharmaceutically acceptable carrier or diluent.
 2. Apharmaceutical sustained release preparation according to claim 1,wherein the galactoxyloglucan is originated from a tamarind seed.
 3. Apharmaceutical sustained release preparation according to claim 1,wherein the preparation is in a dosage form suitable for rectal orvaginal absorption, percutaneous or permucous membrane absorption,intraperitoneal administration or oral administration.
 4. Apharmaceutical sustained release preparation according to claim 1,wherein the preparation is in the form of a suppository.
 5. A method forsustained release of a pharmaceutically active compound, which comprisesadministering a pharmaceutical sustained release preparation comprisinga partial degradation product of the galactose of a galactoxyloglucan,which is produced by subjecting a galactoxyloglucan originating from aplant to an enzymatic hydrolysis and to a galactose removal ratio of30-55%, as a sustained release ingredient together with thepharmaceutically active compound and optionally a pharmaceuticallyacceptable carrier or diluent to a patient in need thereof.
 6. A methodaccording to claim 5, wherein the galactoxyloglucan is originated from atamarind seed.
 7. A method for making a pharmaceutical sustained releasepreparation, which comprises combining a partial degradation product ofthe galactose of galactoxyloglucan, which is produced by subjecting agalactoxyloglucan originating from a plant to an enzymatic hydrolysisand to a galactose removal ratio of 30-55%, as a sustained releaseingredient with a pharmaceutically active compound and optionally apharmaceutically acceptable carrier or diluent.
 8. A method according toclaim 7, wherein the partial degradation product of the galactose of agalactoxyloglucan is originated from a tamarind seed.